This application is for the 5-year renewal of the program project, Healthy Aging and Senile Dementia (HASD), now in its 25th year. In this renewal, there is a continued focus on the clinical, psychometric, and neuropathologic correlates of dementia of the Alzheimer type (DAT) in comparison with healthy aging with a new thrust addressing preclinical Alzheimer's disease. Five interactive and supportive Cores are proposed: Core A: Administration provides administrative support to all components and assures progress in accomplishing program project goals. Core B: Clinical recruits, enrolls, psychometrically and clinically assesses subjects annually to supply all projects. Core C: Biostatistics oversees data management and provides statistical input to all Cores and projects. Core D: Neuropathology performs postmortem examinations for clinicopathological correlation for all studies and provides appropriate tissue and data to Projects as needed. Core E: Neuroimaging collects structural imaging data on our cohort to visualize change in anatomy associated with cognitive decline. Two new projects replace the current Projects 1 and 4, which have been completed. The new Project 1 ("Preclinical AD predicts poststroke dementia" JC Morris) examines the relationship between the presence of amyloid in the brain (as measured by PET PIB) at time of stroke to the later development of dementia. The new Project 4 ("Sequence variation in genes for biomarker proteins and age at onset of Alzheimer's Disease" AM Goate) uses CSF proteins as intermediate traits, or endophenotypes, to identify novel genetic risk factors for late onset DAT. Two current projects will continue in this application to extend their findings and explore new initiatives. Project 2 ("Antecedent biomarkers of AD in CSF and plasma" DM Holtzman) examines whether markers in the CSF and plasma proteome can be combined to develop a more accurate determination of dementia risk in cognitively normal elderly individuals. Project 3 ("Markers for DAT: Control, Variability and Personality," D Balota) will develop cognitive markers as early indicators of DAT. Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease.